HSV-2 (herpes simplex virus-2) is a member of the family Herpetoviridae, a group of DNA viruses that often result in skin lesions (e.g., chickenpox and fever blisters) and are characterized by latent and recurrent infections. HSV-2 is the leading cause of genital ulcers, which can manifest as a cluster of small fluid-filled blisters that rupture and form painful sores, taking several weeks to heal. Additional symptoms may include fever, general sick feeling, muscle aches, painful urination, vaginal discharge, and enlarged, tender lymph nodes in the groin area. Recurring outbreaks are likely. The virus can exist in nerve cells for the life time of the infected subject and reactivate, forming skin ulcers, at irregular intervals. Even in the absence of actual ulcers, the virus can be produced and spread from individual to individual. It is presently incurable.
Genital herpes is the most prevalent sexually transmitted disease. In the United States, over 16% of the population, or about one out of six people, is infected with HSV-2, with a disproportionate burden on women—approximately 20% of women and 12% of men—and on African-Americans—about 40% of the population and nearly 50% of African-American women. (Morbidity and Mortality Weekly Report, 59: 456-459, Apr. 23, 2010). Altogether, about 50 million people in the U.S. are infected, of which about 80% are unaware of their infection, but may still be infectious. Elsewhere in the world, HSV-2 also attains epidemic proportions. A WHO team estimated that in 2003, 536 million people world-wide were infected, and new infections were occurring at about 23 million yearly (Looker et al., Bull World Health Organ. 86: 805-812, 2008). Although prevalence varied by region, generally prevalence increased with age and was higher among women than among men. In addition, HSV-2 prevalence is higher in developing countries than in developed countries—with the exceptions of North America, which has a high HSV-2 prevalence, and south Asia, which has a relatively low HSV-2 prevalence. The highest prevalence is found in Sub-Saharan Africa where nearly 80% of women and 45% of men are infected with HSV-2. Other regions, notably eastern Asia and south-east Asia, approach this level. In addition to sexual transmission, HSV-2 can be transmitted from a woman to a baby, typically at the time of delivery. Concomitant with the HSV-2 epidemic in the adult U.S. population, the incidence of neonatal infection has also dramatically increased. About 1,800 cases of neonatal HSV infection occur yearly in the U.S., which is a higher number of cases than neonatal HIV infection.
The health implications of HSV-2 infection are staggering. Although the vast majority of infected individuals are asymptomatic, virus can still be transmitted. Those with symptoms suffer painful sores on their genitals and anal region and often flu-like symptoms such as fever and swollen glands. Unfortunately, those with a first outbreak of HSV-2 are likely to have several additional outbreaks (typically four or five) within the first year alone. Regardless of the severity of symptoms, knowledge of infection often causes stress and can negatively impact quality of life (Rosenthal, et al., Sex Transm Infect. 82: 154, 2006; Crosby et al Sex Health, 5:279-283, 2008). In neonates infected with HSV-2, neonatal encephalitis from HSV infection has a mortality of >15% even with treatment, and the neurological morbidity among HSV-2 infected infants is an additional 30-50% of surviving cases Coupled with the high prevalence of HSV-2, there is a stark realization that HSV-2 infection substantially increases the risk for HIV-1 acquisition and transmission. Data from Africa show that HSV-2 infection can increase the risk for HIV transmission by as much as seven-fold and that up to one-half of newly acquired HIV cases are directly attributed to HSV-2 infection. Overall, the relative risk of HIV acquisition increases more than two-fold in HSV-2-infected individuals. The synergistic effect on HIV acquisition is greater for HSV-2 than for any other sexually transmitted infection, underscoring the need for an effective public health strategy capable of minimizing the effects of the current HSV-2 epidemic.
The increasing prevalence of HSV-2 in the adult and pediatric populations persists despite the widespread use of pharmacological intervention. Antiviral medication, such as acyclovir, given at high doses early in infection can reduce HSV transmission, but this does not prevent latent infection of the neuronal ganglion. Antiviral therapy has many drawbacks, including as side effects nausea, vomiting, rashes, and decreased kidney function, and should be used with caution because they can be teratogenic as well as be toxic to developing embryos. Furthermore, continuous suppressive administration with valcyclovir reduced HSV transmission by less than 50% despite early intervention. Even if this level of effect were acceptable, the approach is impractical considering the high cost and that 80% of those infected are unaware of their status. Alternatives to antiviral drugs, such as topical microbicides are unproven clinically, and physical barriers (e.g., condoms) have marginal “real-world” efficacy. For these reasons, vaccination is essential for combating and diminishing the health impact of HSV-2 infection.
The first vaccine for HSV was developed in the 1920s, and since then, a variety of vaccine approaches have been tried—all to no avail. The conventional, time-honored types of vaccines including whole, inactivated virus, attenuated live virus, modified live virus, and cell culture-derived subunits were largely unsuccessful or had low efficacy (Stanberry, Herpes 11 (Suppl 3) 161A-169A, 2004). With the advent of recombinant DNA technology, recombinant subunit vaccines have been developed. These vaccines comprised one or two of the envelope glycoproteins in combination with adjuvants. The glycoproteins were attractive candidates mainly because they are the targets of neutralizing antibodies and they are highly conserved among HSV-2 strains. In the last decade, extensive clinical trials on two candidate vaccines, one developed by Chiron and the other by GlaxoSmithKline, were both halted due to insufficient efficacy. Chiron's vaccine comprised truncated forms of two HSV-2 glycoproteins, gD2 and gB2, in combination with the adjuvant MF59. The vaccine at best provided transient protection against HSV-2 although high titers of antibodies to HSV-2 were generated (Stanberry, ibid). GlaxoSmithKline (GSK) developed and tested a similar vaccine; however it contained only a single glycoprotein, gD2, and alum and MPL as adjuvants. Following eight years of studies and clinical trials, GSK pronounced it as a failure in October 2010. The vaccine was unsuccessful in preventing infection in seronegative women, the only group in early clinical trials that had seemed to benefit.